Substituted 4 indazolaminoquinolines

ABSTRACT

Substituted indazolaminoquinolines, acid addition salts thereof as well as N-oxides thereof are anti-inflammatory, antihypertensive and anti-malarial agents. Illustrative embodiments are 7-chloro-4-(6-indazolamino)-quinoline and ethyl 7-chloro-4(6-indazolamino)-quinoline-3-carboxylate.

ite if;

States atent 1 Wasley et a1.

[451 Aug. 28, 1973 SUBSTITUTED 4 INDAZOLAMINOQUINOLINES Inventors: Jan W. F. Wasley, Ossining;

Abraham Wajngurt, Riverdale, both of N.Y.

Assignee: Ciba-Geigy Corporation, Ardsley,

Filed: July 1, 1971 Appl. No.: 159,061

Related [1.8. Application Data Continuation-impart of Ser. No. 818,044, April 21, 1969, abandoned, and a continuation-in-part of Ser. No 725,176, April 29, 1968, abandoned.

US. Cl. 260/288 R, 260/286 R, 260/287 R,

260/289 R, 260/309, 424/258 Int. Cl C07d 33/50 Field of Search 260/287 R, 288 R Primary ExaminerDona1d G. Daus Attorney-Karl 1F. Jorda et a1.

[57] ABSTRACT Substituted indazolaminoquinolines, acid addition salts thereof as well as N-oxides thereof are antiinflammatory, anti-hypertensive and anti-malarial agents. Illustrative embodiments are 7-ch1oro-4-(6- indazo1amino)-quino1ine and ethyl 7-ch1oro-4-(6- indazolamino)-quino1ine-3-carboxy1ate.

16 Claims, No Drawings SUBSTITUTED 4 INDAZOLAMINOQUINOLINES CROSS-REFERENCE This is a continuation-in-part of copending application, Ser. No. 818,044, filed Apr. 21, 1969, and of application, Ser. No. 725,176, filed Apr. 29, 1968, both now abandoned.

DETAILED DESCRIPTION The present invention relates to a novel class of chemical compounds.

More specifically, the present invention pertains to compounds of the general formula wherein R is hydrogen or halogen;

R, is hydrogen, lower alkyl, benzyl, phenyl, pbromophenyl, p-chlorophenyl, carboxy, carbo(- lower alkoxy), or trifluoromethyl;

R and R are each hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, or trifluoromethyl, or R and R are methylenedioxy when combined and adjacent;

R is hydrogen or lower alkyl;

R, is hydrogen, lower alkyl, carboxy or carbo(lower alkoxy);

and pharmaceutically acceptable acid addition salts and N-oxides thereof.

It should be noted that the amino bridge between the indazole moiety and the quinoline, moiety can be attached to the 3-, 4-, 5-, 6-, or 7- position of the indazole moiety. R can be on any of the four ranging free carbon atoms of these positions.

The expression halogen" as used herein is intended to cover chlorine, bromine and iodine, preferred is chlorine; lower alkyl is intended to cover alkyl groups of from one to six carbon atoms such as methyl, ethyl, propyl, butyl, sec.-butyl, pentyl, isopentyl, hexyl, and the' like. The preferred, substituent is methyl; lower alkoxy is intended to cover alkoxy groups containing from one to four carbon atoms such as methoxy, ethoxy, propoxy or butoxy, preferably methoxy and ethoxy.

The expression pharmaceutically acceptable acid addition salts", as used herein, is intended to cover salts of the basic amino compounds, said salts being derived from non-toxic inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric, pamoic, etc.

The expression N-oxides. thereof as used herein is intended to cover compounds of Formula I in which the l-oxide is at the l-position of the quinoline moiety.

The compounds of the present invention may be further substituted by a lower aklyl (methyl) group at either the 2-position of the indazole moiety or at the 1- position of the quinoline moiety. In such a case, the

halogenating R5 agent R, It

Ila

R,, R,, R R,, R, and R, are as defined above and X is halogen, preferably chlorine, bromine, or iodine.

As indicated above, a 4-hydroxyquinoline of Formula II is reacted with a halogenating agent to form the corresponding 4-haloquinoline (Ila). The 4-haloquinoline (Ila) is then condensed with the aminoindazole of choice (III) to yield the hydrohalide salt of the indazolaminoquinoline (IV) which, if desired, may be converted to the free base by treatment with a base in the usual manner.

Where R, or R, is a carboxy moiety, this group may, if desired, be removed by decarboxylation procedures known to the art to form compounds of general Formula I supra wherein R, or R is hydrogen.

Where R, l-Methyl-4-(6-indazolimino)-R in a compound of Formula I is carboxy, the corresponding compound wherein R, and R is carbalkoxy is first prepared and saponified in the usual manner.

In a specific embodiment of the present invention illustrating the preparation of the active compounds, a 4-hydroxyquinoline of general Formula II is reacted with a halogenating agent, such as, a phosphorous pentahalide and illustratively phosphorous pentachloride, by refluxing the reactants in a solution of a phosphorous oxyhalide, in particular, phosphorous oxychloride. After heating for from about I to about 3 hours, the reaction mixture is cooled, and the product isolated.

Generally, the isolation procedure is carried out by quenching the reaction mixture with ice, neutralizing with aqueous ammonia and collecting the solid precipitate thus formed. This solid is thoroughly extracted with hot organic solvents such as ether, or petroleum ether, to yield the 4-haloquinoline of general Formula (lla).

The condensation of the aminoindazole (III) with the 4-haloquinoline (Ila) may be accomplished by any of three general procedures. The two components may be fused together; or they may be heated together in a solvent which is inert to the present reaction, such as acetone, dimethylformamide, dimethylsulfoxide, chloroform, acetonitriie, etc., or the reaction may be carried out in dilute mineral acid such as, for example, dilute hydrochloric acid. While the ratio of reactants is not critical, it is preferred to utilize a 1:1 molar ratio of quinoline to indazole. V

In the fusion process, the components are heated to a temperature of about 130l60C for a period of from about 3 to about 10 minutes. The reaction mixture becomes solid, and is then cooled, dissolved in aqueous alkanol, suitably aqueous ethanol, made basic by the addition of, most suitably, aqueous ammonia and the product precipitated by the addition of water. The product is then removed by filtration and recrystallized most suitably from ethanol or ethyl acetate.

In the procedure involving the use of an inert solvent such as acetone, the reactants are dissolved in dry acetone and heated under reflux for a period of from about one-half to about 40 hours. The reaction mixture is then cooled and the product isolated as the hydrochloride salt. if desired, this hydrochloride salt may be con-- verted to the free base by solution in aqueous alcohol, basification, suitably with aqueous ammonia, and precipitation with water. The precipitate is then collected, dried and recrystallized from a suitable solvent such as ethanol or ethyl acetate.

In the procedure involving the use of a mineral acid such as dilute hydrochloric acid, the components are suspended in dilute hydrochloric acid, suitably from about 0.1N to about 5N acid and heated under reflux from about 2 to about hours. The reaction mixture is cooled, and the hydrochloride salt of the product isolated by filtration. If desired, the hydrochloride salt is then converted into the base in the manner set forth above.

As stated above, the indazolaminoquinolines of the present invention are characterized by antiinflammatory, anti-hypertensive as well as anti-malarial properties. Pharmacological test data has been obtained illustrating the therapeutic activity characterizing the compounds of the present invention. The daily dosages are between about 10 mg/kg and 400 mg/kg of the mammal.

The compounds of the present invention demonstrate the properties of inhibiting and reducing inflammation, of lowering blood pressure and of favorably influencing malaria. They are thus useful as antiinflammatory anti-hypertensive and anti-malarial agents. The anti-inflammatory property of this class of compounds can be conveniently observed in the laboratory model in such art-recognized tests as the turbidity model, U.V. erythema test, anti-carrageenin, and adjuvant arthritis screens. For instance, in the turbidity model test, inhibition of heat coagulation of serum proteins was observed in rats at dosages of mg/kg on subcutaneous administration.

In the anti-carrageenin screen, a diminution of swelling induced by carrageenin was observed in rats at dosages of 50-100 rug/kg p.o.

in the adjuvant arthritis screen protection was observed at dosages of 100 mg/kg when administered orally per day.

The anti-hypertensive properties of the compounds of this invention have been domonstrated in such artrecognized anti-hypertensive tests as the tyrosine hydroxylase inhibition screen, the mouse norepinephrine release screen and tests with unanaesthetized DOCA hypertensive rats.

The compounds of the present invention also exhibit anti-malarial properties. The efiicacy of the compounds was determined in the imidazole N-methyl transferase test. Inhibition was observed at concentrations from between 10 molar to l0 molar.

The indazolaminoquinolines have very favorable therapeutic index; they are active in low concentrations while their LD values are very high.

The indazolaminoquinolines of the present invention are administered topically, parenterally or orally to achieve an anti-inflammatory, anti-hypertensive or anti-malarial effect, in any of the usual pharmaceutical forms. These include solid and liquid unit oral dosage forms such as tablets, capsules, powders, suspension, solutions, syrups and the like, including sustained release preparations, and fluid injectable forms such as sterile solutions and suspensions. When administered topically, the compounds are compounded into pharmaceutically acceptable lotions, creams, ointments, powders or sprays. The term dosage form as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosage form to animals, each unit containing a predetermined quantity of active material in association with the required diluent, carrier or vehicle. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units.

Powders are prepared by comminuting the compound to a suitably fine size and mixing with a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules ae made by preparing a powder mixture as described above and filling formed gelatin sheaths. A lubricant such as talc, magnesium stearate and calcium stearate can be added to the powder mixture as an adjuvant before the filling operation; a glidant such as colloidal silica may be added to improve flow properties; a disintegrating or solubilizing agent may be added to improve the availability of the composition when the capsule is ingested.

Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base such as starch, sucrose, kaolin, dicalcium phosphate and the like. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the

powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dystuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosage form so that a given quantity, e.g., a teaspoonful, contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use of a nontoxic alcoholic vehicle. Suspensions can be formulated by dispersing the composition in a nontoxic vehicle in which it is insoluble.

For parenteral administration, fluid unit dosage forms can be prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium. Alternatively a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. I

One important embodiment of the present invention, particularly for preparing solid pharmaceutical formulations, is the pharmaceutically acceptable non-toxic acid addition salts of these indazolaminoquinolines as well as the N-oxides.

The following examples are given by way of illustrating the procedure used in preparing the compounds of the present invention without limiting the scope thereof in any way. The temperatures are given in degrees Centigrade.

EXAMPLE 1 7-Chloro-4-(6-indazolamino)-quinoline 13.3 g. (0.1 mole) of 6-amino-indazole was suspended in 500 ml. of 3N HCl and to this mixture was added 19.8 g. (0.1 mole) of 4,7-dichloroquinoline and this mixture was refluxed for 8 hours. (Aftr refluxing for one hour, a precipitate appeared which went back in solution after 2 hours. After refluxing for 3 hours, a new precipitate appeared.) The reaction mixture was stirred overnight, then cooled and the hydrochloride salt of the product was collected. The 7-chloro-4-(6- indazolamino)quinoline HCl was dissolved in 400 ml. of alcohol and 200 ml. of water and the solution was treated with charcoal. The clear solution was made basic to a pH 9-10 with 10% NH,OH. The compound that precipitated was collected on a Buchner funnel and washed well with water. After two recrystallizations from ethanol, the product melted at 253-254: Yield 8.0 g. after drying to constant weight for 3 days in vacuum oven at 100 Analysis for C H CIN,

Calc'd.: C, 65.20; H, 3.76; N, 19.07

Found C, 64.94; H, 3.67; N, 18.87

EXAMPLE 2 4-(6-lndazolamino)-quinaldine 13.3 g. (0.1 mole) of 6-amino-indazole was suspended in 750 ml. of 2N HCl. To this mixture was added 17.7 g (0.1 mole) of 4-chloro-quinaldine and the mixture was refluxed for 5 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The 4-(6-indazolamino)quinaldine hydrochloride was dissolved in 500 ml. of water and the pH of this mixture was adjusted to 8-9 with 10% NPLOH. The compound that precipitated was collected on a Buchner funnel and washed well with water and dried over-night in vacuo. After recrystallization from a mixture of ethyl acetate and isopropanol 2:1 using charcoal, the product melted at 240241; Yield 3.8 g. (after drying to constant weight for 3 days in vacuum oven at C). Analysis for C H N Calcd.: C, 74.73; H, 5.14; N, 20.43

Found C, 74.55; H, 4.90; N, 20.36

EXAMPLE 3 4-( 3-lndazolamino )-quinaldine A mixture of 3 g. (0.023 mole) of 3-aminoindazole and 4.07 g. (0.023 mole) of 4-chloro-quinaldine (obtained by the procedure described by A. Bamberger Berichte 55, 3371, (1922) was gently warmed at for period of 5 minutes. The mobile reaction mixture solidified and was then dissolved in a mixture of 200 ml. 50 percent ethanol and basified with 10% NH,OH (pH 9-10). The product was precipitated by the addition of 200 ml. of water. The product was filtered and washed well with water. The compound was recrystallized from ethanol; it melted at 264-265; Yield 4.3 g. Analysis for C H,-,N

Calcd.: C, 74.73; H, 5.14; N, 20.43

Found C, 74.94; H, 4.96; N, 20.58

EXAMPLE 4 4-(6-Chloro-3-indazolamino)-quinaldine A mixture of 8.3 g. (0.05 mole) of 6-chloro-3-aminoindazole and 8.5 g (0.05 mole) of 4-chloroquinaldine was gently warmed at 140 for a period of 5 minutes. The mobile reaction mixture solidified and was then dissolved in a mixture of 200 ml. 50 percent ethanol and basified with 10% NH OH (pH 9-10). The product was precipitated by the addition of 400 ml. of water. The product was filtered and washed well with water. The compound was recrystallized from ethanol. It melted at 23l-233; Yield 6.2 g. Analysis for C H CIN,

Calcd.: C, 66.13; H, 4.24; N, 18.15

Found C, 65.90; H, 4.17; N, 18.35

EXAMPLE 5 4-(5-lndazo1amino)-quina1dine 6.65 g. (0.05 mole) of 5-Aminoindazole was suspended in 220 ml. of 2N HC]. To this mixture was added 8.85 g (0.05 mole) of 4-chloroquinaldine and the mixture was refluxed for 5 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The 4-(5-indazolamino)quinaldine hydrochloride thus obtained was dissolved in 300 m1. of water and the pH of this mixture was adjusted to 8-9 with 10% NH OH. The compound that precipitated was collected on a Buchner funnel and washed well with water and dried overnight in vacuo. After recrystallization from ethyl acetate, the product melted at 298299; Yield 3.1 g. Analysis for C H N,

Calcd.: C, 74.43; H, 5.14; N, 20.43

Found C, 74.18; H, 5.23; N, 20.22

EXAMPLE 6 7-Trifluoromethyl-4-(6-indazolamino)quinoline a. A mixture of 25 g. of 4-hydroxy-7-trifluoromethylquinoline and 150 ml. of phosphorous oxychloride was refluxed with stirring for a period of four hours. The excess POCl was removed in vacuo to give a syrupy residue. This was cooled, 100 ml. of ethanol was added and the mixture was stirred for 30 minutes. The resulting solid was filtered off and suspended in a mixture of alcohol and water; the pH of this mixture was adjusted to 9-10 with Nl-LOH. A crystalline compound precipitated which was filtered off, washed well with water and dissolved in 300 ml. of ether. The ether solution was dried over Na SO,, filtered and concentrated in vacuo to give a crystalline compound identified as 4- chloro-7-trifluoromethylquinoline, m.p. 66-69 (22.3 g.).

b. 7.0 g. (0.053 mole) of 6-Aminoindazole was dissolved in 200 ml. of dry acetone. To this mixture was added 12.0 g. (0.053 mole) of 4-chloro-7-trifluoromethylquinoline obtained above and the mixture was heated under reflux for 36 hours. The reaction mixture was concentrated in vacuo and the hydrochloride salt of the product was collected. The 7-trifluoromethyl-4- (6-indazo1amino)-quinoline hydrochloride was suspended in 200 ml. of a mixture of 50 percent of alcohol and water and made basic with Nl-hOl-l (pH 8-9). The crystalline compound that precipitated was filtered and washed well with water. After crystallization from ethanol, the product melted at 266-268; Yield 4.0 g. Analysis for C H F N,

Calcd.: C, 62.19; H, 3.38; N, 17.06; F, 17.36

Found C, 62.27; H, 3.47; N, 17.00; F, 17.36

EXAMPLE 7 Analysis for C H N,

Calcd.: C, 78.54; H, 4.80; N, 16.6 Found C, 78.30; H, 4.92; N, 16.77

EXAMPLE 8 7-Chloro-4-(5-indazolamino)quinaldine A mixture of 7.3 g. of 4,7-dichloroquinaldine and 4.6 g. of S-aminoindazole were dissolved in 200 ml. of 2 N HCl and heated under reflux for 7 hours. The reaction mixture was allowed to cool overnight and the hydrochloride salt of the product was collected. The 7- chloro-4-(5-indazolamino)quinaldine hydrochloride was suspended in 50 m1. of ethanol and was basified with concentrated NH OH. The suspension was stirred for 30 minutes, the solid product was collected and was washed well with water. After recrystallization from ethyl acetate, the product melted at 300-302. Yield: 2.1 g. Analysis for C l-l ClN Calc'd.: C, 66.13; H, 4.24; N, 18.15

Found C, 65.97; H, 4.47; N, 17.86

EXAMPLE 9 4-(7-lndazolamino)-quinaldine A mixture of 6.1 g. of 7-aminoindazole and 8.1 g. of 4-chloroquinaldine were dissolved in 100 ml. 3N HCl and the solution was heated under reflux for 8 hours. The reaction mixture was allowed to stand overnight and then heated under reflux for an additional 8 hours. The hydrochloride salt of the product was collected and suspended in a mixture of 160 mls. of water and 40 mls. of ethanol and basified with 10% NH,OH. An additional 200 ml. of water were added to ensure complete precipitation of the product, which was collected by filtration. After recrystallization from ethanol, the product melted at 255-257; Yield 3.3 g. Analysis for CH N Calcd.: C, 74.43; H, 5.14; N, 20.43

Found C, 74.71; H, 5.33; N, 20.29

EXAMPLE l0 4-(4-lndazolamino)-quinaldine A mixture of 10 g. of 4-aminoindazole and 13.4 g. of 4-ch1oroquinaldine were dissolved in 100 ml. of 3N RC1 and the solution was heated under reflux for 16 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected, suspended in a mixture of 160 ml. of water and 40 m1. of ethanol and basified with 3N NaOH. The compound that precipitated was collected by filtration and washed well with water. After recrystallization from ethanol using charcoal, the product melted at 274-276. Yield 3.0 g. Analysis for C H N Calcd.: C, 74.43; H, 5.14; N, 20.43

Found C, 74.12; H, 5.08; N, 20.17

EXAMPLE 11 4-(3-Chloro-6-indazolamino)quinaldine A solution of 7.5 g. (0.045 mole) of 6-amino-3- chloroindazole and 7.95 g. (0.045 mole) of 4- chloroquinaldine in 200 m1. of 2N HCl was heated under reflux for 7 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The 4-(3-chloro-6-indazolamino)-quinaldine hydrochloride was suspended in a mixture of 200 ml.

- of ethanol and 200 m1. of water and basified with 3N NaOH. The compound that precipitated was collected by filtration and washed well with water. After two recrystallizations from ethyl acetate, the product was ob tained melting at 269270. Yield: 4.5 g. Analysis for C l-l CIN.

Calcd.: C, 66.13; H, 4.28; N, 18.15

Found C, 66.22; H, 4.51; N, 18.09

EXAMPLE 12 4-( 5-lndazolamino)-7-trifluorornethylquinaldine a. A mixture of 3-trifluorornethylaniline (129.0 g. 0.8 mole) and ethyl acetoacetate (104.2 g., 0.8 moles) was stored in a vacuum dessicator over CaCl, until the water uptake totalled 16.5 g. This mixture was then poured into refluxing phenyl ether (700 ml.). The mixture was boiled under reflux for 40 minutes, cooled to 70 and filtered. The resulting solid was triturated with ether and collected. m.p. 324-330; Yield 16.3 g.

b. A solution of 4-hydroxy-7-trifluoromethyl quinaldine obtained above (16.3 g., 0.072 mole) in POCl was boiled under reflux (oil bath 120) for 1 hour. This solution was cooled, poured onto a mixture of cracked ice and 50% NaOH (200 ml.), the pH was adjusted to -11 and the mixture was extracted with ether; the ether solution was dried over Na SO charcoaled and evaporated to dryness yielding an oil which crystallized on triturating with petroleum ether. Yield: 15.1 g., m.p. 4246.

c. S-Aminoindazole (8.1 g., 0.061 moles) was dissolved in dry acetone and to this solution 4-chloro-7- trifluoromethylquinaldine obtained above (15.1 g., 0.061 mole) was added; the resulting solution was boiled under reflux (oil bath 100) for 1 1 hours precipitating 4-(5-indazolamino)-7trifluoromethylquinaldine hydrochloride. The hydrochloride salt was suspended in EtOH/water (400 ml., 1:3), the suspension was basified with 3N NaOH and filtered; the product was washed well with water. The product melted at 278 after two recrystallizations from ethyl acetate. Yield: 1.4 g.

Analysis for C, H, -,F N

Calcd.: C, 63.15; H, 3.83; N, 16.37 Found C, 63.06; H, 3.94; N, 16.55

EXAMPLE 13 Ethyl 4-(6-indazolamino)quinaldine-3-carboxylate 6-Aminoindazole (1.6 g.) and ethyl 4- chloroquinaldine-3-carboxylate (3.0 g.) were combined and gently warmed. The mobile reaction mixture solidified. This was dissolved in hot ethanol, basified with 10% NH OH, and the product precipitated with water. Recrystallization of the product from aqueous ethanol yielded pale yellow prisms 1.5 g.: 33%), m.p. 226-7. Analysis for C H N O Calcd.: C, 69.35; H, 5.24; N, 16.18

Found C, 69.05; H, 5.30; N, 16.40

EXAMPLE 14 Ethyl 4-(4-indazolamino)-quinaldine-3-carboxylate 4.66 g. (0.035 mole) of 4-Amino-indazole was dissolved in 200 ml. of dry acetone. To this mixture was added 8.7 g. (0.035 mole) of ethyl 4-chloroquinaldine- 3-carboxy1ate and the mixture was refluxed for 24 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The ethyl 4- (4-indazolamino)-quinaldine-3-carboxylate hydrochloride was dissolved in 100 ml. of alcohol and 100 ml. of water and the pH of this mixture was adjusted to 8-9 with 10% NH OH. The compound that precipitated was collected on a Buchner funnel, washed well with water and dried overnight in vacuo. Yield 7.0 g. After two recrystallizations from ethyl acetate (charcoal), the product melted at 177-l78. Yield 3.9 g. after drying to constant weight for 2 days in vacuum oven at 100C. Analysis for C H N O,

Calcd.: C, 69.35; H, 5.24; N, 16.18

Found C, 69.05; H, 5.34; N, 16.06

EXAMPLE 1 5 Ethyl 7-chloro-4-( 6-indazolamino )-quinoline-3 carboxylate a. A mixture of 32.6 g. (0.13 mole) of ethyl 7-chloro- 4-hydroxyquinoline-3-carboxylate, 60 ml. of phosphorous oxychloride and 27 g. (0.13 mole) of phosphorous pentachloride was boiled under reflux for 2 hours and cooled. This mixture was poured slowly wwth stirring onto 1.5 Kg. of ice and 1.5 liters of NH OH keeping the mixture alkaline to phenolphthalein at all times. Stirring was continued for 2 hours and the precipitate was collected by filtration and air dried overnight. The solid was leached with several portions of boiling ether. The ether solution was dried over Na SO and concentrated in vacuo. The crystalline residue was leached with several portions of boiling petroleum ether and the residue was discarded. The petroleum ether extracts were combined, treated with charcoal (KB), concentrated until crystallization began, and then cooled. The colorless crystals that separated were collected by filtration and dried. The product, ethyl 4,7-dichloro-3- quinolinecarboxylate, was obtained in a yield of 10 g., m.p. 78-80. 1n the literature, m.p. 80-82, Edward F. Elslager and coworkers, J. Pharm. Chem., 5, 558 (1962).

b. 4.6 g. (0.035 mole) of 6-aminoindazole was dissolved in 250 ml. of dry acetone. To this mixture was added 9.5 g. (0.035 mole) of ethyl 4,7-dichloro-3- quinoline carboxylate obtained above and the mixture was refluxed for 8 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The ethyl 7-chloro-4(6- indazolamino)quinoline-3-carboxylate hydrochloride was dissolved in a mixture of alcohol and water and the pH- of this mixture was adjusted to 8-9 with 10% NH OH. The compound that precipitated was collected on a Buchner funnel, washed well with water. After two recrystallizations from ethanol and charcoal, the product melted at 208-209. After drying to constant weight for two days in a vacuum oven at yield was 4.0 g.

Analysis for C H CIN O Calcd.: C, 62.21; H, 4.12; N, 15.28 Found C, 62.09; H, 4.00; N, 15.26

EXAMPLE 16 Ethyl 4-(S-indazolamino)-quinaldine-3-carboxylate 4.65 g. (0.035 mole) of S-Aminoindazole was dissolved in 250 ml. of dry acetone. To this mixture was added 8.7 g. (0.035 mole) of ethyl 4-chloroquinaldine- 3-carboxylate and the mixture was refluxed for 8 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. Ethyl 4-(5- indazolamino )-quinaldine-3-carboxylate hydrochloride was dissolved in 500 ml. of 50 percent alcohol and the pH of this mixture was adjusted to 8-9 with 10% NH,OH. The compound that precipitated was collected on a Buchner funnel and washed well with water and dried overnight in vacuo. Alter two recrystallizations from ethyl acetate, the product melted at 225-226. Yield 3.6 g. (after drying to constant weight for three days in vacuum oven at 100). Analysis for C,,H,,N 0,

Calcd.: C, 69.35; H, 5.24; N, 16.18

Found C, 69.41; H, 5.34; N, 16.08

EXAMPLE l7 Ethyl 4-( 7-indazolamino)-quinaldine-3-carboxylate 9.3 g. (0.07 mole) of 7-amino-indazole was dissolved in 500 ml. of dry acetone. To this mixture was added 17.4 g. (0.07 mole) of ethyl 4-chloroquinaldine-3- carboxylate and the mixture was refluxed for 21 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The ethyl 4-(7- indazolamino)-quinaldine-3-carboxylate hydrochloride was dissolved in 500 ml. of 50 percent alcohol and the pH of this mixture was adjusted to 8-9 with 10% Nl-LOH. The compound that precipitated was collected on a Buchner funnel and washed well with water. After two recrystallizations from ethanol the product melted at l97198; Yield 6.5 g. (after drying to constant weight for 2 days in vacuum oven at 80-90). Analysis for C 11 N 0,

Calcd.: C, 69.35; H, 5.24; N, 16.18

Found C, 69.24; H, 5.29; N, 16.28

EXAMPLE 18 Ethyl 7-trifluoromethyl-4-(6-indazolamino)-quinoline- 3-carboxylate a. A mixture of ethyl 4-hydroxy-7- trifluoromethylquinoline-3-carboxylate, 60 ml. of phosphorous oxychloride and 15 g. of phosphorous pentachloride was heated under reflux for 8 hours and cooled. This mixture was poured slowly with stirring into 1.5 Kg. of ice and made basic pH 10-11 with 10N NaOH. Stirring was continued for additional 2 hours and a gummy precipitate was obtained which crystallized upon standing. The crystalline compound was filtered and washed well with water. The solid was leached with 300 ml. of ether. The ether solution was dried over Na SO, and concentrated in vacuo. With the addition of petroleum ether, the compound, ethyl 4- chloro-7-trifluoromethylquinoline-3-carboxylate, crystallized. lt melted at 62-64. Yield: 4.6 g. Analysis for C H ClF N Calcd.: C, 51.41; H, 2.99; N, 4.61

Found C, 51.46; H, 2.99; N, 4.81

b. 1.79 g. (0.0133 mole) of 6-Aminoindazole was dissolved in 100 ml. of dry acetone. To this mixture was added 4.1 g (0.0133 mole) of ethyl 4-chloro-7- trifluoromethyl quinoline-3-carboxylate obtained above and the mixture was refluxed for 7 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The ethyl 7- trifluoromethyl-4-(6-indazolamino)-quinoline-3- carboxylate hydrochloride was dissolved in a mixture of alcohol and water and the pH of this mixture was adjusted to 8-9 with 10% NH OH. The compound that precipitated was collected on a Buchner funnel and washed well with water. After recrystallization from a mixture of cyclohexane and ether, the product melted at 158-l60. Yield 2.4 g. Analysis for C H F N O,

Calcd.: C, 60.00; H, 3.78; N, 13.99

Found C, 59.96; H, 3.80; N, 13.78

EXAMPLE l9 4-(6-lndazolamino)-quina.ldine-3carboxylic acid Methyl acetoacetate (315 g.), isatoic anhydride (300 g.), sodium hydroxide (5 g.) and dioxane (750 ml.) were mixed together with moderate stirring and the mixture was refluxed for a period of 24 hours during which time carbon dioxide was evolved. The reaction mixture was cooled and the product precipitated. The compound, methyl-4-hydroxyquinaldinc-3-carboxylate was filered and washed with ether. Yield: 135 g., m.p. 237-238.

b. 135 g. of methyl 4-hydroxyquinaldine-3- carboxylate obtained above and 450 ml. of phosphorous oxychloride were refluxed for a period of 2 hours. The excess POCl was removed in vacuo to give a syrupy residue. This was cooled, 200 ml. of ethanol was added and the mixture was stirred for 30 minutes. The solid was filtered and dissolved in 500 ml. of water. The pH of this mixture was adjusted to 8-9 with 10% NH,OH. The reaction mixture was extracted with ether The ether extract was washed with water, dried over MgSO, and concentrated in vacuo to give a solid, methyl 4-chloroquinaldine-3-carboxylate, melting at 58-60. Yield 78.8 g.

c. 26.6 g. of 6-Aminoindazole were dissolved in 850 ml. of dry acetone and to this mixture was added 47 g. (0.2 mole) of methyl 4-chloroquinaldine-3-carboxylate obtained above. The mixture was refluxed with stirring for 6 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The salt (methyl 4-(6-indaz0lamino)-quinaldine-3- carboxylate hydrochloride) was dissolved in 400 ml. of 50 percent alcohol and the pH of this mixture was adjusted to 8-9 with 10% NI-LOH. The compound that precipitated was collected on a Buchner funnel and washed well with water. After two recrystallizations from ethanol the product, methyl 4-(6-indazolamino)- quinaldine-3-carboxylate melted at 232233. Yield 30 g.

d. 11 g. (0.033 mole) of methyl 4-(6-indazolamino)- quinaldine-B-carboxylate obtained above was suspended in 100 ml. of 3N NaOH and the reaction mixture was refluxed for a period of 4 hours. The reaction mixture was cooled and 100 ml. of water was added. The aqueous mixture was extracted with ethyl acetate (to remove unreacted ester). The water solution was made acid to pH 3.8 with 3N HCl. The compound precipitated. The precipitate was collected and washed well with water. After recrystallization from 600 ml. of methanol using charcoal, the compound, 4-( 6- indazolamino)quinaldine-3-carboxylic acid, melted at 273-275. Yield: 5.0 g. The same compound was obtained when methyl 4-( 6-indazolamino)-quina1dine-3- carboxylate was hydrolyzed with Lil in pyridine solution. Analysis for C;gH N402 Calcd.: C, 67.92; H, 4.43; N, 17.60

Found C, 67.90; H, 4.23; N, 17.42

EXAMPLE 20 pH of this mixture was adjusted to 10-11 with 3N NaOH. The compound that precipitated was collected on a Buchner funnel and washed well with water. Re-

crystallization from ethanol and charcoal afl'orded a compound which melted at 243245. Yield: 10.4 g. Analysis for C,,,H,,,N O

Calcd.: C, 68.66; H, 4.85; N, 16.86

Found C, 68.40; H, 4.95; N, 16.74

EXAMPLE 21 Methyl 4-(6-indazolamino)-quinaldine-3-carboxylate 26.6 g. of 6-aminoindazole were dissolved in 850 ml. of dry acetone and to this mixture was added 47 g. (0.2 mole) of methyl 4-chloroquinaldine-3-ca.rboxylate. The mixture was refluxed with stirring for 6 hours. The reaction mixture was cooled and the hydrochloride salt of the product was collected. The salt [methyl 4-(6- indazolamino)-quinaldine-3-carboxylate hydrochloride] was dissolved in 400 ml. of 50 percent alcohol and the pH of this mixture was adjusted to 8-9 with 10% NH OH. Thp compound that precipitated was collected on a Buchner funnel and washed well with water. After two recrystallizations from methanol, the product melted at 232-233. Yield: 30 g. Analysis for C H N O Calcd.: C, 68.66; H, 4.85; N, 16.86

Found C, 68.71; H, 5.05; N, 16.93

EXAMPLE 22 7-Chloro-4-(6-indazolamino)-quinoline-3-carboxylic acid A mixture of 3.5 g of ethyl 7-chloro-4-(6- indazolamino)-quinoline-3-carboxylate and 25 ml. of 3N sodium hydroxide was heated under reflux for 3 hours. During this time a yellow solution was obtained, which was then diluted with 75 ml. of water and acidified to pH 6. The solid which precipitated was collected by filtration and then suspended in hot methanol and reflltered to yield a yellow solid, m.p. 289; Yield: 2.4

Analysis for C,,H,,C1N,O I

Calcd.: C, 60.27; H, 3.27; N, 16.54; C1, 10.47 Found C, 60.10; H, 3.43; N, 16.27; Cl, 10.47

EXAMPLE 23 Ethyl 2-phenyl-4-(5-indazolamino)-quinoline-3- carboxylate a. A mixture of 138 g. (0.82 mole) of isatoic anhydride, 253.8 g. (1.31 mole) of ethyl benzoylacetate, 4.6 g. of sodium hydroxide and 530 ml. of p-dioxane were heated under reflux for 8 hours. The solution was cooled; the product, ethyl 2-pheyl-4-hydroxyquinoline- 3-carboxylate, was collected and washed with ether. Yield: 48.5 g., m.p. 252-255.

b. A mixture of 48.5 g. (0.164 mole) of ethyl 2- phenyl-4-hydroxyquinoline-3-carboxylate, obtained above, and 130 ml. of phosphorous oxychloride was heated under reflux for 3 )ihours. The excess phosphorus oxychloride was removed by distillation under reduced pressure, leaving a reddish gum which was dissolved in ethanol. The solution was basified with 3N NaOH and diluted with water. The aqueous solution was extracted with ether and the ethereal extracts were dried over sodium sulfate and evaporated to dryness yielding an oil which crystallized on trituration with petroleum ether. Yield: 40.2 g., m.p. 6265.

c. To a solution of 11.6 g. (0.864 mole) of 5- aminoindazole, dissolved in dry acetone, was added 35.2 g. (0.864 mole) of ethyl 2-phenyl-4- chloroquinoline-3-carboxylate, obtained above The reaction mixture was heated under reflux for 8 hours, and the hydrochloride salt of the product was collected. A suspension of the ethyl 2-phenyl-4-(5-indazolamino)- quinoline-3-carboxylate hydrochloride in a mixture of 150 ml. of water and 15 ml. of ethanol and was basified with 3N NaOH. The compound that precipitated was collected and washed well with water. After two recrystallizations from ethanol, using charcoal, the product melted at 220222. Yield: 5.6 g. Analysis for C H N O Calcd.: C, 73.50; H, 4.94; N, 13.72

Found C, 73.27; H, 4.87; N, 13.76

EXAMPLE 24 Methyl 4-(3-chloro-6-indazolamino)-quinaldine-3- carboxylate a. To a solution of ferrous sulfate (326 g.) in water (400 ml.) was added to a hot solution of 3-chloro-6- nitroindazole (39.4 g., 0.2 mole) in ethanol (410 ml.); concentrated NH Ol-l was then added (246 ml.). This mixture was heated under reflux on the steam bath for 20 minutes, NH,OH (400 ml.) was again added and heating was continued for an additional 20 minutes. The suspension was filtered hot, the salts were washed several times with boiling ethanol, the washings and filtrate were evaporated to dryness in vacuo; the residue was dissolved in ethyl acetate, the solution was dried over Na SO charcoaled and evaporated to dryness, m.p. l77l82; Yield; 24.3 g. (Lit: m.p. 185, Robert R. Davies, J. Chem. Soc. 1955, 2,414).

b. 3-Chloro-6-aminoindazole, obtained above, (13.5 g., 0.08 moles) was dissolved in dry acetone (100 ml.) and then methyl 4-chloroquinaldine-3-carboxylate (17.7 g., 0.08 mole) was added. The resulting solution was boiled under reflux (oil bath, 100) for 8 hours, precipitating methyl 4-(3-chloro-6-indazolamino)- quinaldine-3-carboxylate hydrochloride. The hydrochloride salt was collected, suspended in ethanol, water (400 ml., 1:3), the suspension was basified with 3N NaOH and diluted with water. The precipitate was collected, and washed with water. After two recrystallizations from a mixture of ethyl acetate and methanol with charcoal treatment, the product melted at 258. Yield: 15.1 g.

Calcd.: C, 62.21; H, 4.12; N, 15.28; C], 9.67 Found C, 61.80; H, 3.92; N, 15.12; Cl, 9.63

EXAMPLE 25 Ethyl 4-(S-indazolamino)-quinoline-2-carboxylate S-Amino-indazole (9.2 g., 0.069 mole) was dissolved in dry acetone (125 ml.) with heating and stirring.

6 recrystallized from ethanol. Yield: 1.8 g., m.p. 258.

Analysis for C,,H N O,

Calcd.: C, 68.66; H, 4.85; N, 16.86 Found C, 68.07; H, 4.90; N, 16.70

EXAMPLE 26 7-Chloro-4-(6-indazolamino)-quinoline 0.5 g. of 7-Chloro-4-(6-indazolamino)-quinoline-3- carboxylic acid was suspended in 50 ml. of diphenylether and the mixture was heated under reflux for 70 minutes (reflux temperature approximately 257259). The reaction mixture was cooled to 80 and filtered. The crystalline compound was washed well with ether and was obtained in a yield of 0.35 g. After recrystallization from ethanol, the compound melted at 251-253. The IR spectrum confirmed the structure of the product as set out in Example 1 supra.

EXAMPLE 27 4-(2-methyl-6-indazolamino)-quinaldine 4-Ch1oroquinaldine (4.71 g., 0.0265 moles) was added to a solution of 2-methyl-6-aminoindazole (3.9 g., 0.0265 moles) in hydrochloric acid (3N, 80 ml.) and the resulting solution was heated under reflux for 16 hours. A yellow crystalline solid was precipitated on cooling. This solid was dissolved in dilute ethanol (20% 500 ml.) and the solution was made basic with 3N sodium hydroxide (pl-l 9-11) precipitating a white crystalline product which was collected, washed well with water, recrystallized first from hot ethanol and then recrystallized twice from ethyl acetate/ethanol. Yield: 1.45 g., m.p. 255257. Analysis for C l-l N Calcd.: C, 74.97; H, 5.59; N, 19.44

Found C, 74.57; H, 5.66; N, 19.80

Using the procedure described above, 4-(1-methyl-6- indazolamino)-quinaldine was obtained in a yield of 50-51%, m.p. 330-331(dec.).

EXAMPLE 28 Ethyl 4-hydroxy-7-methylquinoline-3-carboxylate m-Toluidine (53.6 g., 0.5 moles) and diethyl ethoxymethylenemalonate (108.1 g., 0.5 moles) were mixed together and placed in a dessicator under vacuum over anhydrous calcium chloride. (water uptake of 4.9 g.) for 7 days. The resulting crotonate was added to refluxing phenyl ether (500 ml.), the solutionwas heated under reflux for 10 minutes, filtered at 70 and the product was triturated twice in ether (1 liter). There was obtained a yield of 6.1 g., m.p. 275-280 dec.

EXAMPLE 29 Ethyl 4-(5-indazolamino)-7-methylquinoline-3- carboxylate A solution of ethyl 4-hydroxy-7-methylquinoline-3- carboxylate (6.1 g., 0.0264 moles) was heatedunder reflux in phosphorous oxychloride (35 ml.) for 1 hour. The reaction mixture was then poured into cracked ice about 1 liter), the pH was adjusted to 9-11 with 3N sodium hydroxide precipitating a white crystalline compound which was filtered and washed with water. A solution of the product in ether was dried over sodium sulfate/magnesium sulfate, charcoaled and evaporated to dryness yielding a solid on cooling with a melting point of 40-42 (5.7 g.).

'S-Aminoindazole (3.28 g., 0.0247 moles) was dissolved in dry acetone (100 ml.) with heating and stirring. Ethyl 4-chloro-7-methylquinoline-3-carboxylate (5.7 g., 0.0247 moles) obtained above, was added and resulting solution was heated under reflux (oil bath 90) for- 8 hours precipitating a yellow crystalline solid.

The crystals were collected, dissolved in dilute alcohol (200 ml., 50%) and the precipitate was adjusted to a pH of 9-1 1 with 3N sodium hydroxide. 600 ml Of water was added and the resulting precipitate was collected and washed well with water. The compound was first recrystallized from alcohol and after two additional recrystallizations from ethyl acetate, the product melted at 239-240; yield of 2.2 g. Analysis for G l-1 N 0 Calcd.: C, 69.34; H, 5.24; N, 16.17

Found C, 69.00; H, 5.52; N, 15.70

EXAMPLE 30 l-Methyl-4-(b 6-indazolimino)-1 ,4-dihydro-quinaldine A mixture of 4-chloroquinaldine (33.7 g., 0.192 mole) and methyliodide (79 g.) was boiled under reflux in acetonitrile (250 ml.) for 3 hours. T he reaction mixture was cooled, the crystalline salt collected on a Buchner funnel and washed with acetonitrile (1 X 55 ml.). The product, 1-methyl-4-chloroquinaldinium iodide, melted at 226-228C. dec; yield 16.4 g. l-Methyl-4-chloro-quinaldinium iodide 10 g., 0.032 mole) was added to a solution of 6-aminoindazole (4.26 g., 0.032 mole) dissolved in 28 EtOH (500 ml.) and this mixture was boiled under reflux for 20 hours. The reaction mixture was cooled and filtered yielding a yellow solid which was suspended in water/EtOl-l (3:1, 400 ml.); the suspension was basified wth 3N NaOH to PH 8-9. The resulting crystalline compound was collected on a Buchner funnel, washed well with water, (5 X 100 ml.), dissolved in hot methanol, charcoaled twice and then recrystallized from EtOH/MeOl-l 1:1), yielding a yellow crystalline solid (1.8 g., m.p. 299-301).

EXAMPLE 31 7-Chloro-1 -methyl-4-(6-indazolimino)-1 ,4-dihydroquinoline A mixture of 4,7-dichloroquinoline (32.5 g., 0.17

mole) and methyl iodide (42. g., 0.51 mole) was boiled under reflux in 250 ml. of acetonitrile for a period of 2.5 hours. The reaction mixture was cooled and the crystalline salt collected on a Buchner funnel and washed with acetonitrile. The product, 4,7-dichloro-1- methyl-quinoliniumiodide, melted at 258259. Yield: 31.7 g.

The aforesaid product (10 g., 0.031 mole) was added to a solution of G-aminoindazole (4.1 g., 0.031 mole) dissolved in 500 m1. of ethanol and this mixture was boiled under reflux for a period of 24 hours. The reaction mixture was cooled and filtered yielding a solid which was suspended in 300 ml. of 50% ethanol and was basifled with 3N NaOl-l to pH 8-9. The resulting crystalline compound was collected on a Buchner funnel and washed well with water. Afler recrystallization from a mixture of ethanol methanol 1:1 the desired compound melted at 266-267. Yield: 2.8 g. Analysis for C, ld,,C1N

Calcd.: C, 66.12; H, 4.25; N, 18.14

Found C, 66.09; H, 4.54; N, 18.23

EXAMPLE 32 4-( 1-Methyl-5-indazolamino)-quinaldine a. l and 2-Methyl-5-nitroindazoles were prepared and separated as described by I. Barclay et al., J. Chem. Soc., 1941,113.

b. To a solution of 26.4 g of S-nitro-l-methylindazole (0.208 mole) in 1,000 ml of ethanol was added a solution of ferrous sulfate 430 g in 650 ml of hot water, followed by the addition of 500 ml of concentrated ammonium hydroxide. The resulting mixture was heated on a steam bath for 3 hours and 320 ml of concentrated ammonium hydroxide was added at 30 minute intervals. The reaction mixture was filtered hot and the residue was washed with 2,000 ml of hot methanol. The filtrate and the washings were combined and concentrated in vacuo. The residue was extracted with 1,500 ml (6 X 250 ml) of hot ethyl acetate and the solution was dried over Na SO and the solvent was removed under reduced pressure. After recrystallization from water the obtained S-amino-l-methylindazole melted at 151-153. Yield 12.7 g.

c. A mixture of S-amino-l-methylindazole (12.6 g: 0.855 mole) and 4-chloroquinaldine 15.2 g: 0.855 mole) was dissolved in 375 ml of 3 HCl and the solution was heated under reflux for 8 hours. The reaction mixture was reduced to circa 200 ml under reduced pressure and the hydrochloride salt of the product was collected. The salt was suspended in a mixture of 160 ml of water and 40 ml of ethanol and basified with 3 N NaOH solution. An additional 200 ml of water was added to ensure complete precipitation of the product, which was collected by filtration. After recrystallization from the ethyl acetate the obtained 4-(1-methyl- 5-indazolamino)-quinaldine melted at 213-214. Yield 3.4 g.

Analysis for C H N Calcd.: C, 74.97; H, 5.59; N, 19.44 Found C, 74.71; H, 5.46; N, 19.60

EXAMPLE 33 Ethyl 7-chloro-4-(6-indazolamino)-quinaldine-3- carboxylate a. A mixture of 63.8 g of 3-ch1oroaniline and 101.6

g of diethylacetylmalonate was stored in vacuo in a dessicator over anhydrous CaCl, for 10 days. 7.0 g of water was taken up. The resulting crotonate was poured into 500 ml of refluxing diphenyl ether and the mixture was heated under reflux for 40 minutes. Upon cooling to 70C the precipitate was collected by filtration and purified by trituration in a mixture of ether and hexane. After recrystallization from ethanol the obtained ethyl 7-chloro-4-hydroxy-quinaldine-S- carboxylate meltedat 297-300C. Yield 22.7 g.

A mixture of the above product and the isomeric ethyl 5-chloro-4-hydroxyquinaldine-3-carboxylate has been described previously by B.P. Bangdivalo and CM. Desai, J. Ind. Chem. Soc., 31, 555 (1954) utilizing a different procedure.

b. A mixture of 22.7 g of ethyl 7-chloro-4- hydroxyquinaldine-3-carboxylate and 100 m1 of phosphorous oxychloride was heated under reflux for 3 hours. The phosphorous oxychloride was then removed by distillation under reduced pressure. The reaction mixing was cooled and 75 ml of ethanol was added with stirring. The hydrochloride salt which precipitated was collected by filtration and dissolved in 500 ml of dilute ethanol (80 percent). The solution was rendered basic with 3 N NaOl-l. Additional water was added to ensure complete precipitation of the product, which was collected by filtration. The obtained ethyl 4,7-dichloroquinaldine-3-carboxylate melted at 58-61C. Yield 9.8 g.

c. G-Aminoindazole (4.6 g., 0.0345 mole) was dissolved in dry acetone ml) with heating and stirring; ethyl 4,7-dichloroquinaldine-3-carboxylate (9.8 g, 0.0345 mole) dissolved in dry acetone (100 cc) was added to the solution of aminoindazole and the mixture was boiled under reflux for 8 hours precipitating the hydrochloride. After two recrystallizations from dilute alcohol the hydrochloride of ethyl 7-chloro-4-(6 indazolamino)-quinaldine-3-carboxylate melted at 261-263. Yield 4.3 g.

d. The above salt was suspended in dilute alcohol (50%, 250 cc), the solution was basified with Nl-LOl-l and diluted with water. The precipitate was collected and washed well with water. After two recrystallizations from dilute alcohol the title compound was obtained which melted at 214-215. Yield 3.1 g. Analysis for C I-I CIN O Calcd.: C, 63.07; H, 4.50; N, 14.52

Found C, 62.87; H, 4.64; N, 14.86

EXAMPLE 34 Ethyl 4-(2'-methyl-6-indazolamino)quinaldine-3- carboxylate a. A mixture of 600 g (0.611 mole) of 6- nitroindazole, 34.25 g (0.611 mole) of potassium hydroxide, 173.8 g (1.222 mole) of methyl iodide and 800 ml of methanol were heated under reflux for 4 hours. The reaction mixture was poured into 2.5 1 of ice water and the resulting precipitate collected by filtration. The dried precipitate 2-methyl-6-nitroindazole was recrystallized from methanol and melted at l58160C. (Lit. Barclay, J. Chem. Soc. 113 (1941) reported m.p. 159-160C.).

b. 21.1 g, (0.1184 mole) of 2-methyl-6-nitroindazole was dissolved in 450 ml of EtOl-l with heating and stirring. g of FeSO dissolved in 300 ml of hot water was added to the indazole solution followed immediately by the addition of 275 ml of cone. NH,OH. The resulting mixture was heated on the steam bath for 3 hours and 275 ml of concentrated Nl-LOH was added at 30 minute intervals. The reaction mixture was filtered hot; the filter cake was dried overnight in vacuo; the filtrate was concentrated to dryness in vacuo. The filter cake and filtrate residues were combined, extracted with 1,000 m1 (4 X 250 ml) of hot ethyl acetate and the solution was dried over Na,S O /MgS0,, and the solvent removed under reduced pressure. After two recrystallizations from water, the obtained 2-methyl-6- amino-indazole melted at 82-858C. Yield 4.6 g.

c. To a solution of 2-methyl-6-aminoindazole (4.6 g:

0.03122 mole) in dry acetone (75 ml) was added a solution of ethyl 4-chloroquinaldine-3-carboxylate (7.8 g: 0.03122 mole) dry acetone (25 ml) and the resulting mixture was heated under reflux for 8 hours precipitating the hydrochloride salt of ethyl 4-(2-methyl-6- indazolamino)-quina.ldine-3-carboxylate.

This salt was collected and dissolved in 10 percent dil. EtOl-l (500 ml); the solution was cooled and basified with cone. NH OH and diluted with 11,0; the precipitate was collected by filtration and washed well with P1 0.

After two recrystallizations from dilute EtOl-l, the title compound melted at 122-124C. Yield 4.1 g. Analysis for C, H, N,O,

Calcd.: C, 69.98; H, 5.59; N, 15.54 9

Found C, 70.26; H, 5.52; N, 15.88

EXAMPLE 35 Ethyl 4-(fi-indazolamino)-quinaldine-3-carboxylate-1- oxide a. Ethyl 4-chloroquinaldine-3-carboxylate (23.4 g: 0.175 mole) was dissolved in CHCl (250 ml). m- Chloroperbenzoic acid (29.4 g: 0.175 mole) was dissolved in CHCl (250 ml) and added to the quinaldine solution; the resulting mixture was allowed to stand at room temperature for 72 hours.

The reaction mixture was extracted with 5% Na CO (4 X 150 ml), then washed with H (3 X 200 ml). The chloroform solution was dried over K CO and the solvent removed under reduced pressure to yield a residue which crystallized on cooling, and trituration with petroleum ether. Yield 21 g., m.p. 127-129C. The obtained compound was ethyl 4-(6-indazolamino)- quinaldine-3-carboxylate-l-oxide.

b. 6-Aminoindazole (10.01 g.: 0.0753 mole) was dissolved in EtOH (310 ml) and H 0 (45 ml). Ethyl 4- chloroquinaldine-3-carboxylate-l-oxide (20 g.; 0.0753 mole) dissolved in EtOH (50 ml) was added to the indazole solution with drops of concentrated l-iCl. The resulting mixture was refluxed for 24 hours and concentrated in vacuo to a residual solid. This solid was suspended in H O, the suspension was basified with concentrated Nl-1 0l-1, and the resulting precipitate was collected and washed with 11 0.

After two recrystallizations from acetone (1 X charcoal) the title compound melted at 239-240C (dec.). Yield 6.5 g.

EXAMPLE 36 7-Chloro-4-(6-indazolamino)-quinoline-l-oxide a. 4,7-Dichloroquinoline (99 g, 0.5 mole) was dissolved in CHCl (300 ml) at room temperature. m- Chloroperbenzoic acid (80%, 101.4 g, 0.5 mole) suspended in Cl-lCl; (1 liter) was added to the quinoline solution. The resulting mixture was allowed to stand at room temperature for 48 hours. The Cl-lCl, solution was washed with 10% Na,CO solution (3 X 500 ml), then with H 0 (3 X 1 liter), dried over K,CO, and concentrated in vacuo.

Recrystallization from EtOH yielded 37.7 g of 4,7- dichloro-quinoline-l-oxide, m.p. 162-l64C. Lit. Ref: E.F. Elslager et al., .1. Med Chem., 1, 6 1964). Reported m.p. 165-l66C.

b. 6-Aminoindazole (13.7 g, 0.096 mole) was dissolved in EtOH (400 ml) and 11,0 (60 ml). 4,!- Dichloroquinoline-l-oxide (20.6 g, 0.096 mole) suspended in cold EtOH (200 ml) was added to the indazole solution. After the addition of 6 drops of concentrated HCl, the mixture was heated under reflux for 24 hours. The solvent was concentrated in vacuo and the residue was suspended in 11,0 (500 ml). The suspension was stirred with cooling and filtered. The precipitate was suspended in dilute EtOH (20%, 400 m1) and was basified with cone. NH OH, diluted well with 11,0 to give precipitate which was collected.

After two recrystallizations from dilute MeOl-l (1 X charcoal), the title compound melted at 281-283C. Yield 5.4 g.

Analysis for C H CIN O Calcd.: C, 61.84; H, 3.57; N, 18.03 Found C, 61.81; H, 3.46; N, 18.31

EXAMPLE 37 7-Chloro-4 (6-indazolamino)-quinoline fonate 6-Aminoindazole (13.1 g; 0.1 mole) was dissolved in acetonitrile (500 ml) and concentrated hydrochloric acid (1.0 ml) was added. The precipitated hydrochloric salt was dissolved by the addition of dimethylformamide to the mixture. 4,7-Dichloroquinoline (19.8 g; 0.1 mole) was added and the solution was refluxed for 4 hrs. The reaction mixture was cooled to room temperature and the product was filtered off and suspended in ethanol (500 ml) with warming. Concentrated aqueous ammonia was added to pH 9 followed by water (2.0 l). The mixture was cooled and the free base filtered off. This material was vacuum dried (27.6 g) and suspended in ethanol (500 m1) and methanesulfonic acid (8.85 g; 1 equiv.) was added. The solution was evaporated to dryness and the residue was recrystallized from ethanol to give 28.6 g of the methanesulfonate salt. m.p. 253(dec).

EXAMPLE 38 4-(6-lndazolamino)-2-trifluoromethylquinoline Dimethane-sulfonate a. 4-1-1ydroxy-2-trifluoromethylquinoline was prepared by the method of A. S. Dey and M. M. Joulie', .1. 'Heterocyclic Chem., 2, 113 (1965), [2- trifluoromethy1-4-quinolinolsgeneral method a.].

b. 4-Chloro-2-trifluoromethylquinoline was prepared by the method of H. R. Snyder et al, J. Amer. Chem. Soc., 69, 371 (1947). A mixture of phosphorous pentachloride (16.4 g) and phosphorous oxychloride (18.4 g) was heated to 4-hydroxy-2-trif1uoromethylquinoline (16.0 g) was added, and the solution was refluxed for 40 minutes. The solution was evaporated under vacuum and the residue was added to ice water ml). The resultant precipitate was filtered off and recrystallized from aqueous ethanol to give 9.4 g of the 4-chlorocompound.

c. 6-Aminoindazole (9.4 g, 0.033 mole) was dissolved in acetonitrile ml) and concentrated hydrochloric acid (0.33 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (80 ml) to the mixture. 4-Hydroxy- Z-trifluoromethylquinoline (9.4 g; 033 mole) was added and the reaction mixture refluxed for 3% hrs., then cooled to room temperature. The solution was evaporated under vacuum and the residue dissolved in ethanol (400 ml). Concentrated aqueous ammonia was added to pH 9. The mixture was cooled and the free base (1.2 g) was filtered off and vacuum dried. This material was suspended in ethanol (50 ml) and methanesulfonic acid (700 mg, 2 equiv.) was added. The resulting solution was evaporated to dryness and the residue recrystallized from ethanol togive 350 mg of the methanesulfonate. m.p. 2 l8-220.

EXAMPLE 39 2-(4-Chloropheny1)4-(6-indazolamino)quinoline Methanesulfonate l-lemi-ethanol Solvate 6-Aminoindazole (0.66 g, 0.005 mole) was dissolved in acetonitrile (25 ml) and concentrated hydrochloric acid (0.05 ml) was added. The hydrochloride salt was dissolved by the addition of dimethylformarnide (12.5 ml). 4-Chloro-2-(4-ch1orophenyl)quinoline [1.3 g,

Methanesul- 0.005 mole; prepared by the method of RM. Peck, R.K. Preston, and HJ. Creech, J. Amer. Chem. Soc., 81, 3984 (1959)] was added and the solution was refluxed for 3 hr. After cooling, the hydrochloride salt of the product was filtered off and dissolved in 70 percent aqueous ethanol (50 ml). Concentrated aqueous ammonia was added to pH 8; the precipitated free base was filtered off and vacuum dried. This material was suspended in ethanol (25 ml) and methanesulfonic acid (1 equivalent) was added. The solution was evaporated and the residue recrystallized four times from ethanol to give 0.8 g of the hemi-ethanol solvate. The presence of the ethanol was confirmed by NMR; the solvate was stable to prolonged vacuum drying. The compound decomposed at 233.

EXAMPLE 40 7-Chloro-4-(6-indazolamino)quinaldine Methanesulfonate 6-Aminoindazole (1.62 g; 0.012 mole) was dissolved in acetonitrile (61 ml) and concentrated hydrochloric acid (0.12 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (30 ml). 4,7-Dichloroquinaldine [2.6 g, 0.012 mol., prepared by the method of A.1(. Sen and UP. Basu, J. Indian Chem. Soc., 34, 833 (1957)] was added and the solution refluxed for 3 hrs. After cooling, the hydrochloride was filtered off and dissolved in ethanol (100 ml) and water (20 ml). Concentrated aqueous ammonia was added to pH 8, and after refrigeration, the free base was filtered off and vacuum dried (2.0 g). This material was suspended in ethanol (100 ml) and methanesulfonic acid (0.62 g; 1 equiv.) was added. The solution was evaporated and the residue recrystallized from ethanol to give 1.8 g of the methanesulfonate, m.p. 256258.

EXAMPLE 41 4-(6-1ndazolamino)-6-methoxyquinoline Methanesul fonate 6-Aminoindazole (0.66 g; 0.005 mole) was dissolved in acetonitrile (25 ml) and concentrated hydrochloric acid (0.05 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide 12.5 ml) to the mixture, 4-ch1oro-6- methoxyquinoline (1 g; 0.005 mole) was added and the solution was refluxed for 3 hrs. The reaction mixture was cooled, and the product was filtered off then suspended in ethanol (100 ml) with warming. Concentrated aqueous ammonia was added to pH 9 and after refrigeration the free base was filtered off. This material was vacuum dried then suspended in ethanol (50 ml). Methanesulfonic acid (1 equivalent) was added and the resulting solution evaporated to dryness. Recrystallization of the residue from ethanol/ethyl acetate gave the methanesulfonate lg), m.p. 258-260 dec.

EXAMPLE 42 6-Chloro-4-(6-1ndazolamino)-2-phenylquinoline Methanesulfonate One Third Hydrate 6-Aminoindazole (533 mg; 4 m mole) was dissolved in acetonitrile (20 ml) and concentrated hydrochloric acid (0.04 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (10 ml) to the mixture. 4,6-Dichloro-2- phenylquinoline (1.1 g; 4 m mole) was added and the reaction mixture refluxed for 3% hr. then cooled to room temperature. The crystalline material was filtered off and dissolved in a mixture of water (7 ml) and ethanol (33 ml). Concentrated aqueous ammonia was added to pH 9. The mixture was cooled and the free base (1.15 g) was filtered off and vacuum dried. This material was suspended in ethanol (25 ml) and methanesulfonic acid (310 mg) was added. The resulting solution was evaporated to dryness and the residue recrystallized from ethanol/ethyl acetate to give the methanesulfonate, m.p. 290-295 dec.

EXAMPLE 43 4-(6-Indazolarnino)quinoline Methanesulfonate 6-Aminoindazole (4.0 g, 0.03 mole) was dissolved in acetonitrile (150 ml) and concentrated hydrochloric acid (0.3 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylfonnamide ml) to the mixture. 4-Chloroquinoline (4.91 g, 0.03 mole) was added and the reaction mixture was refluxed for 2 hrs. and cooled to room temperature. The crystalline material was filtered off and then dissolved in a mixture of 2B ethanol (100 ml) and water (5 ml) with warming. Concentrated ammonia was added to pH 8, which precipitated the free base. After refrigeration the product was filtered off (3.2 g), and suspended in 2B ethanol (70 ml). Methanesulfonic acid (1.2 g) was added and the resulting solution evaporated to dryness. Recrystallization from ethanol/ethyl acetate gave the methanesulfonate salt (2.6 g), m.p. 224-227.

EXAMPLE 44 4-(6-lndazolamino)-2-phenylquino1ine Methanesulfonate 7 grams (.0208 moles) of 4-(6-indazolamino)-2- phenylquinoline (Ex. 7) was partially dissolved in 100 ml hot ethanol. With the addition of 2 g (0.0208 mole) methanesulfonic acid the solution became homogeneous. Thesolvent was removed under reduced pressure, and the product was recrystallized twice from ethanol/ether to give 6 grams (67 percent) m.p. 3053 10 dec.

EXAMPLE 45 4-(6-lndazolamino )-7-methyl-2-phenylquinoline Methanesulfonate I a. 4-Chloro-7-methyl-2-phenylquinoline was prepared by the method of B.P. Bangdiwala and CM. Desai, J. Indian Chem. Soc., 31, 43 (1954), m.p. 82.

b. 6-Aminoindazole (0.85 g) was dissolved in acetonitrile (35 ml) and concentrated hydrochloric acid (0.07 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (17.5 ml). 4-Chloro-7-methyl-2-phenylquinoline 1.7 g) was added and the reaction mixture was refluxed for 3% hr. The reaction mixture was cooled to room temperature and the crystalline product filtered off, and dissolved in ethanol ml). Concentrated aqueous ammonia was added to pH 8 and the free base was precipitated by the addition of water (200 ml). The free base was suspended in ethanol (50 ml) and methanesulfonic acid (1 equivalent) was added. The solution was evaporated and the residue recrystallized from ethanol to give 1.4 g. of the monomethanesulfonate, m.p. 278-9.

EXAMPLE 46 4-(6-lndazolamino)-6-methoxy-2-phenylquinoline Methane-sulfonate 6-Aminoindazole (3.17 g; 23.8 mM) was dissolved in acetonitrile (125 ml) and concentrated hydrochloric acid (0.24 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (60 ml) to the mixture. 4-Chloro-6-methoxy-2- phenylquinoline (6.4 g; 23.8 mM) [prepared according to the method of B.P. Bangdiwala and C.M. Desai, Jour. Indian Chem. Soc., 31, 43 No. 1 (1954)] was added and the reaction mixture refluxed for 3 hrs. and cooled to room temperature. The precipitated material was suspended in hot ethanol (100 ml) and. concentrated ammonium hydroxide (20 ml) was added to give a clear solution. The free base precipitated on. standing at room temperature (6.6 g) and was dissolved in hot ethanol (100 ml) by the addition of methanesulfonic acid (1.9 g; 1.1 eq). The methanesulfonate salt on recrystallization from ethanol (2 times) gave 4.? g of the pure compound, m.p. 316318.

EXAMPLE 47 4-(6-lndazolamino)-6-hydroxy-2-phenylquinoline Methanesulfonate Monohydrate 4-( 16-Indazolamino )-6-methoxy-2-phenylquinoline hydrochloride (Ex. 46) (2.5 g) was dissolved in 48 percent hydrobromic acid (250 ml) and refluxed for 4 hrs. The crystalline material was filtered off, suspended in ethanol (150 ml) and brought into solution with concentrated ammonium hydroxide (25 ml). The free base was precipitated with water (800 ml), filtered off and dried. it then was dissolved in ethanol (100 ml), methanesulfonic acid 1.0 g) was added, ether was added to the cloud point and the solution was kept in the freezer to give 2.0 g of the pure compound, m.p. 210-212.

EXAMPLE 48 4-(6-lndazolamino)-6-methoxy-2-phenyl-7-trifluoromethylquinoline Methanesulfonate a. 4-Hydroxy-6-methoxy-7-trifluoromethyl-2- phenylquinoline (11.2 g) [prepared by the general procedure of 8.1. Bangdiwala, C.M. Desai, Jour. Indian Chem. Soc. 31, 43 (1954)] was dissolved in phosphorous oxychloride 100 ml) and refluxed for 40 minutes. it was then poured on ice and neutralized with strong ammonia. The precipitate (11.5 g) was filtered off and crystallized from ethanol (900 ml) to give 10.3 g of the pure product, m.p. 172.

b. -Aminoindazole (1.33 g; 10 mM) was dissolved in acetonitrile (50 ml) and concentrated hydrochloric acid (0.1 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (25 ml) to the mixture. 4-Chloro-6-methoxy-7- trifluoromethyl-Z-phenylquinoline (3.37 g; 10 mM) was added and the reaction mixture refluxed for 3 hr. and cooled to room temperature. The precipitated material (3.8 g) was suspended in hot ethanol (100 ml) and concentrated ammonium hydroxide (25 ml) was added to give a clear solution. The free base was precipitated by the addition of 800 ml water. 3.3 g of the free base were suspended in hot ethanol (100 ml), methanesulfonic acid (730 mg; 1 eq) was added to give 3.4 g of the methanesulfonate salt which on recrystallization from ethanol/water (2 times) gave 2.4 g of the pure product, m.p. 340342.

EXAMPLE 49 4-(6-lndazolamino)quinaldine Methanesulfonate 6-Aminoindazole (13.3 g; 0.1 M) was dissolved in acetonitrile (500 ml) and concentrated hydrochloric acid (1.0 ml) was added. The partially precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (250 ml) to the mixture. 4- Chloroquinaldine (17.7 g; 0.1 M) was added and the reaction mixture refluxed for 2% hours and cooled to room temperature. The precipitated material (28.5 g) was dissolved in a hot mixture of ethanol (500 ml) and water ml), concentrated ammonium hydroxide (60 ml) was added to the cooled solution and then diluted with water (2 liters). The precipitated free base (25.0 g) was dissolved in ethanol (650 ml) with wanning and methanesulfonic acid (8.75 g; 1 eq.) was added to yield 29.5 g of the methanesulfonate salt which on recrystallization (3 times) from ethanol gave 15.8 g of the product, m.p. 238,240.

EXAMPLE 50 4-(6-lndazolamino)-6-methoxyquinaldine Methanesulfonate 6-Aminoindazole (6.7 g) was dissolved in acetonitrile (400 ml) and concentrated hydrochloric acid (0.5 ml) was added. The precipitated hydrochloride salt was dissolved by the addition of dimethylformamide (200 ml) to the mixture. 4-Chloro-6-methoxyquinaldine 10.5 g) [Schock, J. Amer. Chem. Soc. 79, 1,672, 1,675 (1957)] was added and the reaction mixture refluxed for 4 hours. The precipitated material (16.5 g) was suspended in ethanol (150 ml), concentrated ammonium hydroxide (30 ml) was added and the free base was precipitated from the clear solution by the addition of water (800 ml). The base (14 g) was suspended in ethanol (150 ml) and methanesulfonic acid (7 g) was added. The precipitated methanesulfonate salt was recrystallized from ethanol (3 times) followed by crystallization from water to give 9 g of the product m.p. 202204. (The m.p. was 300 302 after recrystallization from ethanol).

EXAMPLE 51 2-Benzyl-4-(6-indazolamino)quinoline Methanesulfonate One-Third Hydrate G-Aminoindazole (320 mg) was dissolved in acetonitrile (12 ml) and concentrated hydrochloric acid (0.05 ml) was added. The precipitated hydrochloric salt was dissolved by the addition of dimethylformamide to the mixture. 2-Benzyl-4-chloroquinoline prepared by the method of A.K. Kiang, F.G. Mann, A.F. Prior, and A. Topham, J. Chem. Soc., 1,319 (1956)] (600 mg) was added and the solution was refluxed for 4 hours. The reaction mixture was cooled to room temperature and the product was filtered off and suspended in ethanol (25 m1). Aqueous ammonia was added to pH 9 followed by water (8 ml). The mixture was refrigerated and the free base filtered off. This material was vacuum dried (500 mg) and suspended in ethanol and methanesulfonic acid (137 mg; 1 equiv.) was added. The solution was evaporated to dryness and the residue recrystallized from ethanol to give 650 mg of the methanesulfonate, m.p. 253255 de'c.

EXAMPLE 52 4-(6-lndazolamino)-7-trifluoroquinaldine Methanesulfonate 7.5 g of 6-aminoindazole, 100 ml of acetonitrile, 0.7 m1 of concentrated hydrochloric acid, 50 ml of dimethylformamide and 13.8 g of 4-chloro-7-trifluoromethylquinaldine [prepared according to the procedure of G. Franchi, P. Vigne, Farmaco, Ed. Sci. 22 (11), 923-929 (1967)] were refluxed for 4 hours. The hydrochloride of the product formed a precipitate which was kept in the freezer overnight and the precipitate was filtered off. It was suspended in 200 ml hot ethanol; 35 ml of ammonium hydroxide was added. The free base dissolved to form a clear dark brown solution. 800 ml of water was added and the free base precipitated. The precipitate was taken up in acetone, evaporated and suspended in 100 ml of ethanol. 5.75 g of methanesulfonic acid was added to yield a clear solution which crystallized on cooling and was recrystallized from aqueous ethanol yielding 11.4 g, m.p. 305307.

EXAMPLE 53 4-(6-lndazolamino)-6,7-methylenedioxyquinaldine Methanesulfonate a. 33.5 g of 3,4-methylenedioxyaniline, 32 g of ethylacetoacetate, 100 ml of benzene and 4 drops of concentrated hydrochloric acid were refluxed for hours. 4.5 ml of water was separated and the benzene solution evaporated. A dark red oil, 62.3 g, was obtained which crystallized, m.p. 80-82.

b. 150 ml of diphenylether was refluxed. 63 g of the product (a) was dissolved in 60 ml diphenylether and added dropwise within 25 minutes. Precipitation took place during cyclization; heating was continued for 3% hours. The reaction mixture was kept at room temperature overnight. The precipitate was filtered off and washed with petroleum ether. 4-hydroxy-6,7- methylenedioxyquinaldine as a brown powder, 44 g, m.p. 347 dec. was obtained.

c. g of 6,7-Methylenedioxy-4-hydroxyquinaldine and 700 ml of phosphorus oxychloride were refluxed for hours. A clear brown solution formed. Excess phosphorus oxychloride was evaporated. The pH was adjusted to 7 with ammonium hydroxide. The precipitation was filtered off and washed with water. The product was recrystallized from a 200 ml methanol/70 ml water mixture. 8.2 g m.p. 13013l of the product was obtained.

d. 3.7 g of 6-Aminoindazole, 75 ml of acetonitrile, 0.33 ml of concentrated hydrochloric acid, 30 ml of dimethylformamide and 6.1 g of 4-chloro-6,7- methylenedioxy-2-methylquinoline were refluxed for 4% hours. The precipitate was kept overnight at room temperature and then filtered off, yielding 9.8 g, m.p. 365 dec. it was suspended in 150 ml of hot ethanol; 50 ml of ammonium hydroxide was added. The free base dissolved to fonn a clar solution. 800 ml of water was added and the free base precipitated after a few min utes, yielding 9.1 g, m.p. 256-258. It was suspended in 200 ml ethanol, heated, and 3.3 g of methanesulfonic acid was added to form a clear solution which precipitated after a few minutes. It was dissolved by adding 100 ml ethanol/50 ml water, yielding 7.6 g, m.p. 288-290.

EXAMPLE 54 7-Fluoro-4-( 6-indazolamino )quinaldine fonate Methanesul- 5 6-Aminoindazole 13.6 g (0.103 m) was dissolved in 500 ml acetonitrile, 1.0 ml concentrated hydrochloric acid was added, 250 ml dimethylformamide added to dissolve the hydrochloride salt, and 4-chloro-7- fluoroquinaldine [prepared by procedure of A.K. Sen,

10 U.P. Basu, J. Ind. Chem. Soc. 37, 836-838 (1957)] was 15 free base was filtered off. It was suspended in 500 ml of ethanol and 8.7 g of methanesulfonic acid was added. The solution was evaporated to dryness and the residue was recrystallized in ethanol/ether, m.p. 309-31l.

What is claimed is:

1. A compound of the formula l N E R5 t R3 l NIH:

wherein R is hydrogen or halogen;

R, is hydrogen, primary and secondary lower alkyl of one to six carbon atoms, benzyl, phenyl, pbromophenyl, p-chlorophenyl, or trifluoromethyl; each of R, and R is hydrogen, hydroxy, halogen, primary and secondary lower alkyl of one to six carbon atoms, lower alkoxy of one to four carbon atoms, or when R, is hydrogen, R is also trifluoromethyl; or R, and R, are methylenedioxy when combined and adjacent;

R is hydrogen or lower alkyl of one to six carbon atoms;

R, is hydrogen or primary and secondary lower alkyl of one to six carbon atoms, and wherein the amino bridge is attached to indazole at the 3-, 4-, 5-, 6- or 7- position; the pharmaceutically acceptable acid addition salts, or the N-oxides thereof, wherein the oxide is at the 1-position of the quinoline moiety.

2. A compound as defined in claim 1 which is 4-(5- indazolamino)-quinaldine.

3. A compound as defined in claim 1 which is 4-( 6- chloro-3-indazolamino)-quinaldine.

4. A compound as defined in claim 1 which is 4-(6- indazolamino)-quinaldine.

S. A compound as defined in claim 1 which is 4-(6- indazolamino)-2-trifluoromethylquinoline.

6. A compound as defined in claim 1 which is 2-(4- chlorophenyl)-4-(6-indazolamino)quinoline. I

7. A compound as defined in claim 1 which is 7.-

chloro-4-(6-indazolamino)quinaldine.

8. A compound as defined in claim 1 which is 4-(6- indazolamino)-6-methoxyquinoline.

28 indazolamino)-6-methoxyQ-phenylquinoline.

14. A compound as defined in claim 1 which is 4-(6- indazolamino)-6-hydroxy-2phenylquinoline.

15. A compound as defined in claim I which is 4-(6- indazolamino)-6-methoxy-2phenyl-7-trifluoromethylquinoline.

16. A compound as defined in claim 1 which is 4-(6- indazolamino )quinaldine. 

2. A compound as defined in claim 1 which is 4-(5-indazolamino)-quinaldine.
 3. A compound as defined in claim 1 which is 4-(6-chloro-3-indazolamino)-quinaldine.
 4. A compound as defined in claim 1 which is 4-(6-indazolamino)-quinaldine.
 5. A compound as defined in claim 1 which is 4-(6-indazolamino)-2-TRIFLUOROMETHYLQUINOLINE.
 6. A compound as defined in claim 1 which is 2-(4-chlorophenyl)-4-(6-indazolamino)quinoline.
 7. A compound as defined in claim 1 which is 7-chloro-4-(6-indazolamino)quinaldine.
 8. A compound as defined in claim 1 which is 4-(6-indazolamino)-6-methoxyquinoline.
 9. A compound as defined in claim 1 which is 6-chloro-4-(6-indazolamino)-2-phenylquinoline.
 10. A compound as defined in claim 1 which is 4-(6-indazolamino)quinoline.
 11. A compound as defined in claim 1 which is 4(6-indazolamino)-2-phenylquinoline.
 12. A compound as defined in claim 1 which is 4-(6-indazolamino)-7-methyl-2-phenylquinoline.
 13. A compound as defined in claim 1 which is 4-(6-indazolamino)-6-methoxy-2-phenylquinoline.
 14. A compound as defined in claim 1 which is 4-(6-indazolamino)-6-hydroxy-2-phenylquinoline.
 15. A compound as defined in claim 1 which is 4-(6-indazolamino)-6-methoxy-2-phenyl-7-trifluoromethyl-quinoline.
 16. A compound as defined in claim 1 which is 4-(6-indazolamino)quinaldine. 